title: Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California.
abstract: California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.
authors.affiliation: Genetic Disease Screening Program, California Department of Public Health, Richmond, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Prach
authors.forename: Ruth
authors.initials: R
authors.lastname: Koepke
authors.forename: Martin
authors.initials: M
authors.lastname: Kharrazi
authors.forename: Steven
authors.initials: S
authors.lastname: Keiles
authors.forename: Danieli B
authors.initials: DB
authors.lastname: Salinas
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Reyes
authors.forename: Mark
authors.initials: M
authors.lastname: Pian
authors.forename: Harry
authors.initials: H
authors.lastname: Opsimos
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Otsuka
authors.forename: Karen Ann
authors.initials: KA
authors.lastname: Hardy
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Milla
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Zirbes
authors.forename: Bradley
authors.initials: B
authors.lastname: Chipps
authors.forename: Susan
authors.initials: S
authors.lastname: O'Bra
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Saeed
authors.forename: Reddivalam
authors.initials: R
authors.lastname: Sudhakar
authors.forename: Susan
authors.initials: S
authors.lastname: Lehto
authors.forename: Dennis
authors.initials: D
authors.lastname: Nielson
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Shay
authors.forename: Mary
authors.initials: M
authors.lastname: Seastrand
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jhawar
authors.forename: Bruce
authors.initials: B
authors.lastname: Nickerson
authors.forename: Christopher
authors.initials: C
authors.lastname: Landon
authors.forename: Ann
authors.initials: A
authors.lastname: Thompson
authors.forename: Eliezer
authors.initials: E
authors.lastname: Nussbaum
authors.forename: Terry
authors.initials: T
authors.lastname: Chin
authors.forename: Henry
authors.initials: H
authors.lastname: Wojtczak
mesh_terms: D000465:Algorithms; D000483:Alleles; D002140:California; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D015997:Neonatal Screening
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator